Date Published: December 18, 2009
Publisher: Public Library of Science
Author(s): Rajendra Kumar Singh, David Lau, Colleen M. Noviello, Partho Ghosh, John C. Guatelli, Peter Sommer. http://doi.org/10.1371/journal.pone.0008364
Abstract: The down-regulation of the major histocompatibility complex class I (MHC-I) from the surface of infected cells by the Nef proteins of primate immunodeficiency viruses likely contributes to pathogenesis by providing evasion of cell-mediated immunity. HIV-1 Nef-induced down-regulation involves endosomal trafficking and a cooperative interaction between the cytoplasmic domain (CD) of MHC-I, Nef, and the clathrin adaptor protein complex-1 (AP-1). The CD of MHC-I contains a key tyrosine within the sequence YSQA that is required for down-regulation by Nef, but this sequence does not conform to the canonical AP-binding tyrosine-based motif Yxxφ, which mediates binding to the medium (μ) subunits of AP complexes. We previously proposed that Nef allows the MHC-I CD to bind the μ subunit of AP-1 (μ1) as if it contained a Yxxφmotif.
Partial Text: Human immunodeficiency virus type 1 (HIV-1) Nef is a 27 kDa protein with no known enzymatic activity that appears to function by mediating protein interactions. Nef contributes to high levels of replication and the pathogenesis of primate lentiviruses such as HIV-1 and Simian Immunodeficiency Virus. Nef is expressed in abundance early during the viral replication cycle, and it down-regulates major histocompatibility complex class I (MHC-I) glycoproteins from the surface of infected cells. Nef has several functions in addition to the down-regulation of MHC-I molecules , such as the removal of CD4 from the surface of infected cells , . The Nef-mediated down-regulation of MHC-I and CD4 is dependent on specific sequences in the cytoplasmic domains of these target proteins , . In the case of MHC-I, Nef induces not only internalization from the plasma membrane but also the retention and degradation of MHC-I within the endo-lysosomal system . Nef also affects signaling through the T-cell receptor CD3 in T-lymphocytes . To perform these functions, Nef associates with the plasma membrane and various endosomal membranes via N-terminal myristoylation .